ALS is paradigmatic of neurodegeneration and is the commonest neurodegenerative disorder of young and middle aged adults. The incidence of ALS in Ireland is 2.6/100,000. 10% of patients with ALS have a family history with an autosomal dominant pattern of inheritance and gain-of-function mutations in the SOD1 gene account for 20% of these. Although the pathogenesis is unknown, there is evidence that genetically determined susceptibility factors may contribute to the development of both ALS and other non-familial neurodegenerative diseases.
Mice with deletions of the hypoxia responsive element (HRE) of vascular endothelial growth factor (VEGF) have a 40% reduction in neural expression and adult-onset motoneuron degeneration, resembling an ALS phenotype. In addition to its angiogenic properties, VEGF has direct neurotrophic and neuroprotective effects on motoneurons and other central neurons. These observations suggest that insufficient VEGF dependent neurotrophic support may be of importance in the pathogenesis of ALS in this animal model.
Genotype meta-analysis of over 1,900 individuals from Northern Europe has identified a relative risk of 1.8 for the development of ALS in subjects homozygous with respect to two haplotypes in the VEGF promoter/leader sequence. The at-risk haplotypes reduce VEGF transcription and result in lowered serum VEGF levels. To date, no mutations in the VEGF HRE or coding sequences have been identified in patients with ALS, and the significance of low circulating VEGF levels remains to be determined.
The only evidence based treatment developed to date for ALS is riluzole, which extends life expectancy by approximately 3 months. The survival effect of riluzole wanes within 18 months of treatment.